In Vitro Simulation of the Fasted Gastric Conditions and Their Variability to Elucidate Contrasting Properties of the Marketed Dabigatran Etexilate Pellet-Filled Capsules and Loose Pellets.

Variability of the gastrointestinal tract is rarely reflected in in vitro test protocols but often turns out to be crucial for the oral dosage form performance. In this study, we present a generation method of dissolution profiles accounting for the variability of fasted gastric conditions. The workflow featured 20 biopredictive tests within the physiological variability. The experimental array was constructed with the use of the design of experiments, based on three parameters: gastric pH and timings of the intragastric stress event and gastric emptying. Then, the resulting dissolution profiles served as a training data set for the dissolution process modeling with the machine learning algorithms. This allowed us to generate individual dissolution profiles under a customizable gastric pH and motility patterns. For the first time ever, we used the method to successfully elucidate dissolution properties of two dosage forms: pellet-filled capsules and bare pellets of the marketed dabigatran etexilate product Pradaxa. We showed that the dissolution of capsules was triggered by mechanical stresses and thus was characterized by higher variability and a longer dissolution onset than observed for pellets. Hence, we proved the applicability of the method for the in vitro and in silico characterization of immediate-release dosage forms and, potentially, for the improvement of in vitro-in vivo extrapolation.

Discriminative Dissolution Method Using the Open-Loop Configuration of the USP IV Apparatus to Compare Dissolution Profiles of Metoprolol Tartrate Immediate-Release Tablets: Use of Kinetic Parameters.

The use of the USP IV apparatus (flow-through cell) has gained acceptance in recent years due to its versatility and ability to discriminate due to its hydrodynamic conditions. Therefore, the objective of the present study was to develop a discriminative dissolution method in the USP IV apparatus using the open-loop configuration, as well as to propose a method to compare non-cumulative dissolution profiles obtained in the open-loop configuration considering kinetic parameters and validate its predictive power through its comparison with independent and dependent methods using five commercial immediate-release tablet drugs (one reference drug and four generic drugs) of metoprolol tartrate as a model drug. The comparison of the non-accumulated dissolution profiles consisted of determining the geometric ratio of Cmax, AUC0∞, AUC0Cmax, and Tmax (kinetic parameters) of the generic/reference drugs, whereby generic drugs "C" and "D" presented the highest probability of similarity since their 90% confidence intervals were included, or they were very close to the acceptance interval (80.00-125.00%). These results were consistent with the f2, bootstrap f2, and dissolution efficiency approaches (independent models). In conclusion, the proposed comparison method can be an important tool to establish similarity in dissolution profiles and to facilitate the development/selection of new formulations and positively ensure bioequivalence in clinical studies.

A Rational Approach to Predicting Immediate Release Formulation Behavior in Multiple Gastric Motility Patterns: A Combination of a Biorelevant Apparatus, Design of Experiments, and Machine Learning.

Gastric mechanical stress often impacts drug dissolution from solid oral dosage forms, but in vitro experiments cannot recreate the substantial variability of gastric motility in a reasonable time. This study, for the first time, combines a novel dissolution apparatus with the design of experiments (DoE) and machine learning (ML) to overcome this obstacle. The workflow involves the testing of soft gelatin capsules in a set of fasted-state biorelevant dissolution experiments created with DoE. The dissolution results are used by an ML algorithm to build the classification model of the capsule's opening in response to intragastric stress (IS) within the physiological space of timing and magnitude. Next, a random forest algorithm is used to model the further drug dissolution. The predictive power of the two ML models is verified with independent dissolution tests, and they outperform a polynomial-based DoE model. Moreover, the developed tool reasonably simulates over 50 dissolution profiles under varying IS conditions. Hence, we prove that our method can be utilized for the simulation of dissolution profiles related to the multiplicity of individual gastric motility patterns. In perspective, the developed workflow can improve virtual bioequivalence trials and the patient-centric development of immediate-release oral dosage forms.

Comparación de los perfiles de disolución de los comprimidos de Losartán potásico 100mg nacionales e importados vs precio, Paraguay (2019)

RESUMEN La hipertensión arterial es el principal factor de riesgo cardiovascular, y su prevalencia en Paraguay es la mayor de América Latina. El objetivo del presente trabajo fue comparar productos de losartán de 100 mg comprimidos de producción nacional e importada a través de los perfiles de disolución versus su precio. Se tomaron 8 marcas de losartán potásico comercializadas durante el 2017, realizándose los controles de calidad de acuerdo a lo establecido en la Farmacopea Americana (USP 38). Se determinó el porcentaje de principio activo liberado en el medio de disolución establecido por la USP 38, por medio de los perfiles de disolución. Las determinaciones se realizaron por HPLC y espectrofotometría UV/V. Los controles realizados cumplieron con las especificaciones establecidas por la USP 38. No se encontraron diferencias significativas en el análisis estadístico de los perfiles de disolución de las diferentes marcas analizadas. Los resultados demostraron que los precios de las marcas analizadas no afectaban la calidad de los productos, pero sí en el costo del tratamiento de la población de escasos recursos, debido al mayor costo de los productos importados con respecto a los de producción nacional.

ABSTRACT Hypertension is the main cardiovascular risk factor, and its prevalence in Paraguay is the highest in Latin America. The objective of the present work was to compare products of 100 mg losartan tablets made in Paraguay and imported products, through dissolution profiles versus price. Eight brands of potassic losartan commercialized during 2017 were subjected to quality controls in accordance with the provisions of the American Pharmacopoeia (USP 38). The percentage of active principle released in the dissolution medium established by USP 38 was determined by means of dissolution profiles. The determinations were made by HPLC and UV/V spectrophotometry. The controls carried out complied with the specifications established by USP 38. No significant differences were found in the statistical analysis of the dissolution profiles of the different brands analyzed. The results showed that the prices of the brands analyzed did not affect the quality of the products, but they affected the cost of treatment of the low-income population due to the higher cost of imported products compared to those of national production.

Estimators and confidence intervals of f2 using bootstrap methodology for the comparison of dissolution profiles.

BACKGROUND AND OBJECTIVES: The most widely used method to compare dissolution profiles is the similarity factor f2. When this method is not applicable, the confidence interval of f2 using bootstrap methodology has been recommended instead. As neither details of the estimator nor the types of confidence intervals are described in the guidelines, the suitability of five estimators and fourteen types of confidence intervals were investigated in this study by simulation. METHODS: One million individual dissolution profiles were simulated for the reference and test populations with predefined target population f2 values, where random samples of different sizes were drawn without replacement. From each pair of random samples, five f2 estimators were calculated, and fourteen types of confidence intervals were obtained using 5000 bootstrap samples. The whole process was repeated 10000 times and the percentage of the similarity conclusions was measured. In addition, the uncertainty associated with the current practice of using f^2 point estimate alone for the statistical inference was evaluated. RESULTS: When combined with different types of confidence intervals, the estimated f2 (f^2), the bias-corrected f2 (f^2,bc), and the variance- and bias-corrected f2 (f^2,vcbc) are not suitable estimators due to higher-than-acceptable type I errors. The estimator f^2,exp, calculated based on the mathematical expectation of f^2, and f^2,vcexp, the variance-corrected f^2,exp, showed acceptable type I errors when combined with any of the ten percentile intervals. However, they have the drawback of low power, which might be addressed by increasing the sample size. To properly control the type I error, samples with at least 12 units should be used. CONCLUSION: The best combinations of estimator and type of confidence interval are f^2,exp and f^2,vcexp combined with any of the ten types of percentile intervals. When the sample f2 value is close to 50, the use of the confidence interval of f2 is recommended even when the variability of the dissolution profiles is low and the prerequisites defined in the regulatory guidelines for using the conventional f2 method are fulfilled in order to control the type I error rate.

Development and optimisation of simulated salivary fluid for biorelevant oral cavity dissolution.

Drug release within the oral cavity can be of paramount importance for formulations that are designed for specific purposes such as taste-masking, faster onset of therapeutic action, localization of treatment or avoidance of first-pass metabolism. Preclinical methods for assessment of dissolution in the oral cavity are necessary for design and development of these formulation but currently there is no consensus on what variables should be defined to achieve biorelevance in these tests. In this study, biorelevant simulated salivary fluids (SSFs) that can be uniformly applied for oral cavity dissolution testing were developed. Unstimulated saliva (US) SSF and stimulated saliva (SS) SSF were separately developed since the two states significantly differ. Physicochemical properties including pH, buffer capacity, surface tension and viscosity were assessed during development and optimised to mimic human saliva (HS). In order to account for the salivary proteins in HS, use of bovine submaxillary mucin (BSM) and porcine gastric mucin (PGM) in SSFs was evaluated. Following optimisation of the SSFs, biorelevance of the developed SSFs to HS was assessed by their comparative physicochemical properties as well as dissolution profiles of three diverse model compounds (sildenafil citrate, efavirenz, and caffeine) which showed comparable profiles between the SSFs and HS. This work addresses the lack of uniformed biorelevant dissolution media for oral cavity dissolution studies and provides a basis for standardised dissolution tests that provide consistency and harmonisation in future oral cavity dissolution studies. We envisage that this will have a positive impact on the development of new medicines that require functionality in the oral cavity.

Solubility, Permeability, and Dissolution Rate of Naftidrofuryl Oxalate Based on BCS Criteria.

The Biopharmaceutics Classification System (BCS) was conceived to classify drug substances by their in vitro aqueous solubility and permeability properties. The essential activity of naftidrofuryl oxalate (NF) has been described as the inhibition of the serotonin receptors (5-HT2), resulting in vasodilation and decreasing blood pressure. Since the early 1980s, NF has been used to treat several venous and cerebral diseases. There is no data available on the BCS classification of NF. However, based on its physical-chemical properties, NF might be considered to belong to the 1st or the 3rd BCS class. The present study aimed to provide data concerning the solubility and permeability of NF through Caco-2 monolayers and propose its preliminary classification into BCS. We showed that NF is a highly soluble and permeable drug substance; thus, it might be suggested to belong to BCS class I. Additionally, a high dissolution rate of the encapsulated NF based on Praxilene® 100 mg formulation was revealed. Hence, it might be considered as an immediate-release (IR).

Regulatory assessment of drug dissolution profiles comparability via maximum deviation.

In drug development, comparability of dissolution profiles of 2 different formulations is usually assessed using the similarity factor f2 . In practice, the drug dissolution profiles are deemed similar if the f2 exceeds 50, which occurs when a 10% maximum difference in the mean percentage of the dissolved drug at each time point between test and reference formulation is obtained. According to the Guideline on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev. 1/ Corr **) use of the f2 is however restricted by a set of validity conditions. If some of these conditions are not satisfied, the f2 is not considered suitable, and alternative statistical methods are needed. In this article, we propose an inferential framework based on the maximum deviation between curves to test the comparability of drug dissolution profiles. The new methodology is applicable regardless whether the validity criteria of the f2 are met or not. Contrary to the f2 , this approach also integrates the variability of the measurements over time and not only their average. To benchmark our method, we performed simulations informed by 3 real case studies provided by the European Medicines Agency and extracted from dossiers submitted to the Centralised Procedure for Marketing Authorisation Application. In the scenarios of the simulation study, the new method controlled its type I error rate when the maximum deviation was greater than the similarity acceptance limit of 10%. The power exceeded 80% for small values of the maximum deviation, while the test was more conservative for intermediate ones. Our results were also very robust to sampling variations. Based on these positive findings, we encourage applicants to consider the new maximum deviation-based method as a valid alternative to the f2 , especially when the validity criteria of the latter are not met.

Application of the Stable Isotope Label Approach in Clinical Development-Supporting Dissolution Specifications for a Commercial Tablet Product with Tafenoquine, a Long Half-life Compound.

Bioavailability/bioequivalence studies supporting clinical drug development or commercial supply of drug formulations are often time, cost, and resource intensive. The drug's pharmacokinetic (PK) variability, systemic half-life, and safety issues may pose additional challenges. The stable isotope label (SIL) approach provides a useful tool to significantly reduce the study size in clinical PK studies. Tafenoquine (TQ) is an 8-aminoquinoline under development for preventing Plasmodium vivax malaria relapse. This SIL study assessed the impact of differences in the in vitro dissolution profiles on in vivo exposure of TQ tablets. Fourteen healthy volunteers received a single dose of 300 mg TQ Intermediate Aged or 300 mg TQ Control formulations in this single-center, two-arm, randomized, open-label, parallel-group study. Endpoints included the geometric means ratio of the area under the concentration-time curve (AUC(0-t) and AUC(0-∞); primary endpoint) and maximum plasma concentration (Cmax) for Intermediate Aged versus Control TQ; correlation of PK parameters for venous versus peripheral (via microsample) blood samples; and safety and tolerability endpoints. Geometric mean ratios for PK parameters (AUC and Cmax) and their 90% confidence intervals fell well within standard bioequivalence limits (0.80-1.25). Only one mild adverse event (skin abrasion) was reported. In summary, this SIL methodology-based study demonstrates that the observed differences in the in vitro dissolution profiles between the Control and Intermediate Aged TQ tablets have no clinically relevant effect on systemic TQ exposure. The SIL approach was successfully implemented to enable the setting of a clinically relevant dissolution specification. CLINICAL TRIAL: This study (GSK study number 201780) is registered at clinicaltrials.gov with identifier NCT02751294.

Solving the Delivery Problems of Triclabendazole Using Cyclodextrins.

Triclabendazole is the first-line drug of choice to treat and control fasciolasis, a neglected parasitic human disease. It is a class II/IV compound according to the Biopharmaceutics Classification System. Thus, the aim of this study was to improve aqueous solubility and dissolution rate of triclabendazole complexed with 2-hydroxylpropyl-ß-cyclodextrin (HP-ß-CD) and methyl-ß-cyclodextrin (Me-ß-CD) at 1:1 and 1:2 M ratio. The impact of storage on the solubility, dissolution profile, and solid-state properties of such complexes was also investigated. Drug-carrier interactions were characterized by infrared spectroscopy, differential scanning calorimetry, X-ray diffractometry, and scanning electron microscopy. The solubility of triclabendazole improved up to 256- and 341-fold using HP-ß-CD and Me-ß-CD, respectively. In particular, the drug complexed with Me-ß-CD showed a positive deviation from linearity, suggesting that its solubility increases with an increasing concentration of Me-ß-CD concentration in a nonlinear manner. The drug dissolution was found to be improved through complex formation with HP-ß-CD and Me-ß-CD. In particular, the 1:2 M ratio complexes exhibited higher dissolution than the corresponding 1:1 M ratio complexes. The physicochemical characterization of the systems showed strong evidence of amorphous phases and/or of the formation of an inclusion complex. Stored at 25 °C, 60% RH for 24 months, drug complexed with ß-cyclodextrins (CDs) at 1:2 M ratio remained amorphous. Based on these findings, it is postulated that the formation of triclabendazole-CD inclusion complexes produced significant enhancement in both the dissolution and solid-state properties of the drug, which may lead to the development of triclabendazole novel formulations with improved biopharmaceutical characteristics.

Comparison between the dissolution profiles of nine meloxicam tablet brands commercially available in Buenos Aires, Argentina.

In this work, the dissolution profiles of nine meloxicam tablet brands marketed in Argentina have been evaluated. As meloxicam is a Class 2 Biopharmaceutical Classification System (BSC) drug, interchangeability between commercial products must be demonstrated through in vivo bioequivalence studies. However, in our country, such studies remain to be performed. Dissolution studies have been performed according to USP 38 and evaluated by fitting experimental data to the zero and first-order, the Hixson-Crowell, the Higuchi, and the Weibull model-dependent methods. To test the pertinence of these release models, the Akaike Information Criteria (AIC) were used. All brands satisfied the dissolution profiles (phosphate buffer, pH 7.5) established in the USP. The comparison between the dissolution profiles was carried out by model-dependent and model-independent methods. The Weibull model provided the best kinetic curve adjustment. Brands I, II, IV and VI had the best fitting, with the maximum determination coefficient and the smallest AIC values. Model-independent methods included ratio test and the fit factors. The Dissolution Efficiency (DE) and Mean Dissolution Time (MDT) were analysed with ANOVA and the DGC method. In both cases, brand I did not show similarity with the rest of the brands. Using fit factors, only brands I, II and V were similar to each other. Significant differences were found among the in vitro dissolution profiles of meloxicam tablets belonging to the nine brands. As meloxicam is a class 2 BCS drug, interchangeability between commercial products must be demonstrated through in vivo bioequivalence studies. However, in Argentina, such studies remain to be performed. Our results demonstrate that caution must be exercised as regards interchangeability of generic products.

Double-Track Electrochemical Green Approach for Simultaneous Dissolution Profiling of Naproxen Sodium and Diphenhydramine Hydrochloride.

Acquisition of the dissolution profiles of more than single active ingredient in a multi-analyte pharmaceutical formulation is a mandatory manufacturing practice that is dominated by utilization of the off-line separation-based chromatographic methods. This contribution adopts a new "Double-Track" approach with the ultimate goal of advancing the in-line potentiometric sensors to their most effective applicability for simultaneous acquisition of the dissolution profiles of two active ingredients in a binary pharmaceutical formulation. The unique abilities of these sensors for real-time measurements is the key driver for adoption of "green analytical chemistry" (GAC) principles aiming to expand the application of eco-friendly analytical methods With the aim of performing a side-by-side comparison, this work investigates the degree of adherence of ISEs to the 12 principles of GAC in multicomponent dissolution profiling with respect to the HPLC. For the proof of concept, a binary mixture of naproxen sodium (NAPR) and diphenhydramine hydrochloride (DIPH) marketed as Aleve pm® tablets was selected as a model for which dissolution profiles were attained by two techniques. The first "Double-Track" in-line strategy depends on dipping two highly integrated membrane sensors for continuous monitoring of the dissolution of each active pharmaceutical ingredient (API) by tracing the e.m.f change over the time scale. For the determination of NAPR, sensor I was developed using tridodecyl methyl ammonium chloride as an anion exchanger, while sensor II was developed for the determination of DIPH using potassium tetrakis (4-chlorophenyl) borate as a cation exchanger. The second off-line strategy utilizes a separation-based HPLC method via off-line tracking the increase of peak area by UV detection at 220nm over time using a mobile phase of acetonitrile: water (90:10) pH 3. The advantages of the newly introduced "Double-Track" approach regarding GAC principles are highlighted, and the merits of these benign real-time analyzers (ISEs) that can deliver equivalent analytical results as HPLC while significantly reducing solvent consumption/waste generation are described.

Evaluation of dissolution profile similarity - Comparison between the f2, the multivariate statistical distance and the f2 bootstrapping methods.

A simulation study is presented, evaluating the performance of the f2, the model-independent multivariate statistical distance and the f2 bootstrap methods in the ability to conclude similarity between two dissolution profiles. Different dissolution profiles, based on the Noyes-Whitney equation and ranging from theoretical f2 values between 100 and 40, were simulated. Variability was introduced in the dissolution model parameters in an increasing order, ranging from a situation complying with the European guidelines requirements for the use of the f2 metric to several situations where the f2 metric could not be used anymore. Results have shown that the f2 is an acceptable metric when used according to the regulatory requirements, but loses its applicability when variability increases. The multivariate statistical distance presented contradictory results in several of the simulation scenarios, which makes it an unreliable metric for dissolution profile comparisons. The bootstrap f2, although conservative in its conclusions is an alternative suitable method. Overall, as variability increases, all of the discussed methods reveal problems that can only be solved by increasing the number of dosage form units used in the comparison, which is usually not practical or feasible. Additionally, experimental corrective measures may be undertaken in order to reduce the overall variability, particularly when it is shown that it is mainly due to the dissolution assessment instead of being intrinsic to the dosage form.

Preparation of Curcumin-Lysine Cocrystal and Solubility Comparison of Different Crystal Forms / 中国药师

Objective:To develop a new cocrystal form to improve bioavailability and druggability of curcumin. Methods:Solvent crystallization was used to prepare curcumin-lysine cocrystal, and two crystal forms ( a and b) were obtained. The two cocrystal forms were characterized by elemental analysis, differential scanning calorimetry and X-ray diffraction. The dissolution profiles of the two crystal forms were detected and compared with that of curcumin. Results:Curcumin combined with lysine at a stoichiometry of 1: 1 to form the cocrystal with much better solubility than curcumin. Conclusion: Curcumin-lysine cocrystal has ideal druggability, which means the cocrystal can be a new chemical entity used for subsequent development.

Regulatory Perspectives on Strength-Dependent Dissolution Profiles and Biowaiver Approaches for Immediate Release (IR) Oral Tablets in New Drug Applications.

Dissolution profile comparisons are used by the pharmaceutical industry to assess the similarity in the dissolution characteristics of two formulations to decide whether the implemented changes, usually minor/moderate in nature, will have an impact on the in vitro/in vivo performance of the drug product. When similarity testing is applied to support the approval of lower strengths of the same formulation, the traditional approach for dissolution profile comparison is not always applicable for drug products exhibiting strength-dependent dissolution and may lead to incorrect conclusions about product performance. The objective of this article is to describe reasonable biopharmaceutic approaches for developing a biowaiver strategy for low solubility, proportionally similar/non-proportionally similar in composition immediate release drug products that exhibit strength-dependent dissolution profiles. The paths highlighted in the article include (1) approaches to address biowaiver requests, such as the use of multi-unit dissolution testing to account for sink condition differences between the higher and lower strengths; (2) the use of a single- vs. strength-dependent dissolution method; and (3) the use of single- vs. strength-dependent dissolution acceptance criteria. These approaches are cost- and time-effective and can avoid unnecessary bioequivalence studies.

Statistical comparison of dissolution profiles.

Statistical methods to assess similarity of dissolution profiles are introduced. Sixteen groups of dissolution profiles from a full factorial design were used to demonstrate implementation details. Variables in the design include drug strength, tablet stability time, and dissolution testing condition. The 16 groups were considered similar when compared using the similarity factor f2 (f2 > 50). However, multivariate ANOVA (MANOVA) repeated measures suggested statistical differences. A modified principal component analysis (PCA) was used to describe the dissolution curves in terms of level and shape. The advantage of the modified PCA approach is that the calculated shape principal components will not be confounded by level effect. Effect size test using omega-squared was also used for dissolution comparisons. Effects indicated by omega-squared are independent of sample size and are a necessary supplement to p value reported from the MANOVA table. Methods to compare multiple groups show that product strength and dissolution testing condition had significant effects on both level and shape. For pairwise analysis, a post-hoc analysis using Tukey's method categorized three similar groups, and was consistent with level-shape analysis. All these methods provide valuable information that is missed using f2 method alone to compare average profiles. The improved statistical analysis approach introduced here enables one to better ascertain both statistical significance and clinical relevance, supporting more objective regulatory decisions.

Determinação das curvas de absorção, perfis de dissolução e estabelecimento de correlação in vitro-in vivo por métodos in silico utilizando o GastroPlusTM e o DDDPlusTM / Determination of absorption curves, dissolution profiles and establishment of in vitro-in vivo correlation by in silico methods using GastroPlusTM and DDDPlusTM

O uso de programas de computador para prever a absorção de fármacos em humanos e simular perfis de dissolução tem se tornado uma ferramenta bastante valiosa na área farmacêutica. O objetivo deste trabalho foi utilizar métodos in silico por meio dos programas de computador GastroPlusTM e DDDPlusTM para simular curvas de absorção de fármacos, perfis de dissolução e estabelecer correlações in vitro-in vivo (CIVIVs). O material aqui apresentado é constituído por cinco capítulos incluindo os fármacos cetoprofeno, pirimetamina, metronidazol, fluconazol, carvedilol e doxazosina. No capítulo 1 são apresentadas curvas plasmáticas simuladas para comprimidos matriciais de cetoprofeno, sendo estabelecida a CIVIV. A utilização de simulações de ensaios de dissolução intrínseca para os fármacos pirimetamina e metronidazol como uma ferramenta para classificação biofarmacêutica é detalhada no capítulo 2. No capítulo 3, a simulação de curvas plasmáticas a partir de cápsulas de fluconazol contendo diferentes perfis de dissolução é demonstrada como uma ferramenta para bioisenção. Estudos de CIVIV foram também realizados para comprimidos de liberação imediata de carvedilol a partir dos perfis de dissolução no capítulo 4. Já o capítulo 5 trata da aplicação de simulações de ensaios de dissolução para o desenvolvimento de formulações de liberação prolongada de doxazosina. As simulações das curvas plasmáticas, assim como a CIVIV, obtidas com o auxílio do programa GastroPlusTM, além dos ensaios de dissolução intrínsica e os perfis de dissolução obtidos por meio do uso do programa DDDPlusTM apresentaram-se como ferramentas de grande aplicação na previsão de características biofarmacêuticas sobre os fármacos e formulações, permitindo redução de tempo e custo com trabalho experimental em laboratório

The use of computer programs to predict drug absorption in humans and to simulate dissolution profiles has become a valuable tool in the pharmaceutical area. The objective of this study was to use in silico methods through software GastroPlusTM and DDDPlusTM to simulate drug absorption curves and dissolution profiles, and to establish in vitro-in vivo correlations (IVIVCs). The work presented herein is divided into five chapters and includes the drugs ketoprofen, pyrimethamine, metronidazole, fluconazole, carvedilol and doxazosin. In Chapter 1, simulated plasma curves for ketoprofen matrix tablets are presented and IVIVC was established. The use of simulated intrinsic dissolution tests for pyrimethamine and metronidazole as a tool for biopharmaceutics classification is detailed in Chapter 2. In Chapter 3, simulation of plasma curves for fluconazole capsules with different dissolution profiles is demonstrated as a tool for biowaiver. IVIVC studies were also conducted for carvedilol immediate-release tablets from dissolution profiles in Chapter 4. Chapter 5 covers the application of simulated dissolution tests for development of doxazosin extended-release formulations. Simulation of plasma curves and IVIVC using the software GastroPlusTM as well as intrinsic dissolution tests and dissolution profiles using the software DDDPlusTM proved to be a tool of wide application in predicting biopharmaceutical characteristics of drugs and formulations, allowing the reduction of time and costs of experimental laboratory work

Similarity Evaluation of Dissolution Profiles of Self-development and Original Preparation of Solifenacin Suc-cinate Tablet / 中国药房

OBJECTIVE:To explore the similarity of dissolution profiles of self-development and original preparation of Solife-nacin succinate tablet,and provide reference for the prescription and process screening of the former one and the quality similarity evaluation of the latter one. METHODS:The paddle method was adopted with rotational speed of 50 r/min,using water,pH1.2 hy-drochloric acid solution,pH4.0 acetate buffer solution and pH6.8 phosphate buffer solution as dissolution media,HPLC was used to determine the cumulative dissolution of main components of self-development and original preparation of Solifenacin succinate tablet at different time points,dissolution profile was drew,then f2 was used to evaluate its similarity. RESULTS:In the 4 dissolu-tion media,the f2 of both self-development and original preparation of Solifenacin succinate tablet was higher than 50,which indi-cated that the dissolution profiles showed similarity. CONCLUSIONS:The established HPLC is suitable for the dissolution determi-nation of Solifenacin succinate tablet;the dissolution profiles of the self-development and original preparations are basically simi-lar,which indicates the prescription and technology of self-development preparation are feasible.

Formulation of spray congealed microparticles with self-emulsifying ability for enhanced glibenclamide dissolution performance.

PURPOSE: To develop a novel preparation approach of solid Self-Emulsifying Drug Delivery System (s-SEDDS) based on spray congealing as potential drug delivery technology for poorly water-soluble drug Glibenclamide (GBD). METHODS: Several systems were formulated using suitable excipients, solid at room temperature, with different hydrophilic-lipophilic balance, such as Myverol, Myvatex, Gelucire®50/13 and Gelucire®44/14. Cremophor®EL and Poloxamer 188 were selected as surfactants and PEG 4000 as co-solvent. RESULTS: The screening of the best carrier for s-SEDDS manufacturing revealed that Gelucire®50/13 had greater performance. Then, surfactant-co-solvent systems were developed. Dissolution studies showed that all the formulations promoted the solubilisation performance of the GBD with respect to pure drug; in particular the formulation containing Gelucire®50/13 and PEG 4000 increased the drug solubilisation of five times. These microparticles showed self-dispersibility within 60 min and micelles dimensions around 360 nm. CONCLUSIONS: Spray congealing is a promising novel manufacturing technique of solid self-emulsifying systems.

Multivariate equivalence tests for use in pharmaceutical development.

Statistical equivalence analyses are well-established parts of many studies in the biomedical sciences. Also in pharmaceutical development and manufacturing equivalence testing methods are required in order to statistically establish similarities between machines, process components, or complete processes. This article presents a choice of multivariate equivalence testing procedures for normally distributed data as generalizations of existing univariate methods. In all derived methods, variability is interpreted as nuisance parameter. The use of the proposed methods in pharmaceutical development is demonstrated with a comparative analysis of dissolution profiles.